Morphine and diamorphine salts of anionic non-narcotic analgesics of the substituted carboxylic acid type

ABSTRACT

The present invention relates to morphine and diamorphine salts of anionic non-narcotic analgesics belonging to the type of substituted carboxylic acids, preferably the morphine and diamorphine salts of diclofenac (Formula 1); to processes for their production, the use of these salts in the treatment of diseases, as well as to pharmaceutical preparations comprising these salts.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to morphine and diamorphine salts ofanionic non-narcotic analgesics belonging to the type of substitutedcarboxylic acids, preferably the morphine and diamorphine salts ofdiclofenac (Formula 1). The present invention further relates toprocesses for their production, the use of these salts in the treatmentof diseases, as well as to pharmaceutical preparations comprising thesesalts.

BACKGROUND OF THE INVENTION

Pain is one of the most frequent signs of a disease or a damage. Thoughpain is to be understood as a warning and protective function of theorganism, patients concerned generally call for pain-killing or at leastpain-relieving substances. For this reason, one of the most importantconcerns in medicine is to provide such substances. The function ofthese substances, so-called analgesics, is to reduce or suppress thesensation of pain when given in therapeutic doses without having ageneral narcotic effect in these doses. Based on their potency,therapeutic mechanism and side effects one distinguishes between twogroups of analgesics: very potent analgesics acting on the centralnervous system and low to moderately potent ones primarily having aperipheral action. Active substances acting on the central nervoussystem frequently involve a habit-forming potential which might developinto addiction. Morphine (Formula 3a) is one example of an activesubstance acting on the central nervous system and having such a risk.In the form of its inorganic salts, for example its hydrochloride orsulfate, morphine is commercially available for parenteral or peroralapplication to control acute posttraumatic or postoperative pain, aswell as chronic pain, for example, in the state of advanced cancer.

A derivative of morphine, diacetylmorphine (Formula 3b), also known asdiamorphine or heroin, is dealt and consumed among drug addicts withoutany pharmacological, pharmaceutical, or pharmacokinetic control. Itsqualified use in the treatment of drug addiction is a scientific andsociological problem that has not yet been solved.

In order to reduce the risk of morphine dependence in the clinical useof morphine preparations, other analgesics, preferably non-narcoticperipheral preparations, are administered at the same time oralternately. Owing to the great variety of peripherally effectiveanalgesics, their different potency and thus their different dosage,there is a great uncertainty concerning the choice of preparations to becombined, resulting in patient discomfort because of the amount of drugsto be taken.

SUMMARY OF THE INVENTION

It is the object of the present invention to provide new analgesicshaving a maximum analgesic effect with minimum side effects.

This object is achieved by the new active substances characterized inthe claims and by the pharmaceutical preparations comprising theseactive substances.

The active substances according to the present invention are themorphine and diamorphine salts of anionic non-narcotic analgesics of thetype substituted carboxylic acids. Suitable anionic non-narcoticanalgesics belonging to the type of substituted carboxylic acidsinclude: diclofenac, indomethacin, sulindac, ketoprofen, or fenbufen.

The present invention preferably includes the salts morphine-diclofenate(Formula 1a) and diamorphine-diclofenate (Formula 1b) consisting of theanionic peripheral analgesic diclofenac([2-[(2,6-dichlorophenyl)-amino]-phenyl]-acetic acid (Formula 2)) andthe cationic analgesic morphine (Formula 3a) acting on the centralnervous system or its derivative diacetylmorphine (Formula 3b), alsoreferred to as diamorphine. In Formula 1, R may represent H or CH₃ CO.If R stands for H, it is morphine-diclofenate (Formula 1a); if R standsfor CH₃ CO, it is diamorphine-diclofenate (Formula 1b). ##STR1##

The above-mentioned non-narcotic analgesics of the type substitutedcarboxylic acids and their salts are known. The sodium, potassium,diethylammonium salts of diclofenac (Formula 2)([2-[2,6-dichlorophenyl)-amino]-phenyl]-acetic acid) are used, forexample, in the treatment of painful inflammatory processes.Preparations for the oral, rectal, parenteral, or topical applicationhave been on the market for some time.

Diclofenac (Formula 2) has proved to be the most potent non-steroidanti-inflammatory agent/analgesic owing to the effective dose and totalclearance. ##STR2##

When applied perorally, diclofenac (Formula 2) is clinicallypharmacologically effective in the dosage range of 0.08 to 0.16 mmol/8hrs., and it is therefore in the range of the molar dosage of morphine(Formula 3a). For comparison: Morphine is effective in the dosage rangeof 0.035 to 0.35 mmol/6 hrs. ##STR3##

In Formula 3 R may be H (morphine) or CH₃ CO (diamorphine)

The salts according to the present invention which are composed of thebase of the narcotic analgesic of Formula 3, wherein R stands for H orCH₃ CO, and the acid of the non-narcotic analgesic of the typesubstituted carboxylic acids, preferably morphine ordiamorphine-diclofenate (Formula 1a or 1b), make it advantageouslypossible to use the individual components in a smaller dose as comparedwith preparations of single-entity drugs in the form of their inorganicsalts in free combination with conventional commercial administrationforms.

The salts according to the present invention, preferably morphine ordiamorphine-diclofenate (Formula 1a or 1b), may be used instead ofclassical morphine preparations to alleviate pain, but with less sideeffects. In the case of the diclofenates according to the presentinvention, the gastrointestinal tolerance limits of diclofenac (Formula2) represent a safeguard for observing the officially recommended dose.For that reason, potential drug abuse inherent in the availability ofmorphine preparations is rendered more difficult by the morphine ordiamorphine salts according to the present invention. The morphine ordiamorphine salts according to the present invention enable thephysician to include the patient in a scheme of treatment, since lessdrugs can be combined freely and less unprofessional variations of themedical recommendation are possible.

The diamorphine salts according to the present invention make itpossible for the first time to include diamorphine in a therapy.

The topical preparations of the salts according to the presentinvention, in particular those of morphine-diclofenate (Formula 1a) anddiamorphine-diclofenate (Formula 1b), allow minimum active substancesupply with reduced systemic side effects, for example, during thewithdrawal phase in addiction therapy.

DETAILED DESCRIPTION

The active substances according to the present invention are producedfrom acid or base components known per se. It is preferable to reactnon-narcotic analgesics of the type substituted carboxylic acids, inparticular [2-[(2,6-dichlorophenyl)-amino]-phenyl]-acetic acid ofFormula 2 or a base salt thereof, with preferably at least the equimolaramount of morphine (Formula 3a) or the morphine derivative according toFormula 3b or a suitable salt thereof. Suitable salts of non-narcoticanalgesics of the type substituted carboxylic acids particularly includesalts of bases which can easily be removed from the reaction mixture.These include, for example, bases which are more volatile or weaker thanmorphine or diamorphine (Formula 3a or 3b), or those forming solublesalts with the anionic non-narcotic analgesic of the type substitutedcarboxylic acids, in particular[2-[(2,6-dichlorophenyl)-amino]-phenyl]-acetic acid of Formula 2, morereadily than the salts according to the present invention do. Thesesalts are other organic ammonium salts, for example. Metallic saltswhich, during the reaction with a suitable acid salt of morphine ordiamorphine (Formula 3a or 3b), form poorly soluble salts of this acidcan also be used as salts, for example, calcium salts.

Salts of morphine or diamorphine (Formula 3a or 3b) suitable to be usedin the process include, for example, salts with acids which may beeliminated from the reaction mixture, e.g., salts of volatile acids. Itis also possible to use acids which are weaker than the non-narcoticanalgesic of the type substituted carboxylic acids, or which form poorlysoluble salts with metal cations, for example Ca²⁺. Salts of morphine ordiamorphine (Formula 3a or 3b) include, for example, salts of thecompounds according to Formula 3a or 3b with inorganic acids, e.g.,hydrochlorides, sulfates, or phosphates, or salts of morphine ordiamorphine (Formula 3a or 3b) and organic acids, e.g., fumarates,maleates, or oxalates.

It is preferable to carry out the reaction of the non-narcoticanalgesics of the type substituted carboxylic acids, preferably[2-[(2,6-dichlorophenyl)-amino]-phenyl]-acetic acid (Formula 2), with abase of Formula 3 in an inert solvent. If necessary, the reaction may becarried out under cooling or heating, for example, in a temperaturerange of about 0 to about 100° C., preferably at room temperature.Reaction may be conducted in a closed vessel and/or under inert gasatmosphere, e.g., in nitrogen atmosphere.

Suitable inert solvents include, for example, alcohols, ethers, ketones,carboxylic acid esters, amides, sulfoxides, chlorinated hydrocarbons, ormixtures of these solvents. Low alkanols may be used as alcohols,preferably methanol or ethanol; di-low-alkyl ethers, preferably diethylethers, cyclic ethers, preferably dioxan or tetrahydrofuran may be usedas ethers; di-low-alkyl ketones, preferably acetone may be used asketones; low-alkyl carboxylic acid esters, preferably acetic acid ethylester may be used as carboxylic acid esters; N,N-di-low-alkyl amides,preferably N,N-dimethylformamide may be used as amides; di-low-alkylsulfoxides, preferably dimethyl sulfoxide may be used as sulfoxides; andmethylene chloride or chloroform may be used as chlorinatedhydrocarbons.

Non-narcotic analgesics of the type substituted carboxylic acids, inparticular [2-[(2,6-dichlorophenyl)-amino]-phenyl]-acetic acid (Formula2), may also be formed under the reaction conditions from thecorresponding esters, preferably low-alkyl esters, by hydrolysis in thepresence of a base, for example, NaOH. Morphine or diamorphine ofFormula 3a or 3b may also be released under the reaction conditions fromthe acid salts, preferably from hydrochlorides, sulfates, or phosphates,in the presence of stoichiometric amounts of suitable bases, forexample, NaOH.

According to a preferred embodiment of the process, the non-narcoticanalgesic of the type substituted carboxylic acids is directly reactedas a free acid according to formula 2 with morphine or diamorphine ofFormula 3a or 3b in the form of a base in a suitable solvent. Thepresent invention also relates to those production processes wherein thestarting materials are manufactured in situ or wherein a startingmaterial is obtained under the reaction conditions from a derivativeand/or is used in the form of a mixture, e.g., in the case of morphineor diamorphine (Formula 3a or 3b) as a raw alkaloid mixture. The presentinvention also includes processes wherein liquid or solid charged oruncharged inorganic or organic adsorbents are used. For example, ionexchangers may be used to bind the cationic or anionic component of thesalts according to the present invention which are subsequently reactedwith the complementary anionic or cationic component. It is alsopossible to use uncharged inorganic or organic adsorbents to prepare orpurify the salts according to the present invention.

Moreover, the present invention relates to pharmaceutical preparationswhich, in addition to pharmaceutical adjuvants known per se, comprisethe salts of morphine (Formula 3a) or diacetylmorephine (Formula 3b) andanalgetically effective carboxylic acids, in particular the salts ofFormula 1a and 1b, morphine-diclofenate or diamorphine-diclofenate. Thepresent invention also relates to methods for the production of thesepharmaceutical preparations. The pharmaceutical preparations accordingto the present invention relate to preparations for enteral, e.g., oralor rectal administration; parenteral, e.g., intravenous, intramuscular,or subcutaneous application; or for topical application, which comprisethe salts according to the present invention, in particular the salts ofFormula 1a and 1b, either alone or together with pharmaceuticallyapplicable carriers, in particular those suitable for controlled activesubstance release.

In standard dosage forms for peroral use the content of the activesubstance according to the present invention preferably ranges betweenof 10 and 90%. To produce tablets or coated tablet cores, the activesubstance is combined, for example, with solid powdery carriers, such aslactose, saccharose, sorbitol, mannitol, starches or amylopectin;cellulose derivatives, gelatin, or polyvinyl pyrrolidone, optionally byadding lubricants, such as magnesium or calcium stearate or polyethyleneglycols; as well as with highly dispersed silicic acid. Cores of coatedtablets are coated, for example, with concentrated sugar solutions whichmay optionally comprise additives, such as gum arabic, talc and/ortitanium dioxide, or with a lacquer dissolved in highly volatile organicsolvents or solvent mixtures. Dyes may be added to these coatings, forexample, to mark different active substance doses. Further suitable oralforms of administration include hard capsules made of gelatin and softclosed capsules made of gelatin and a softener, such as glycerol. Thefirst-mentioned preferably comprise the active substance as a granularmaterial mixed with lubricants, such as talc or magnesium stearate, andoptionally with stabilizers, such as sodium pyrosulfite (Na₂ S₂ O₅) orascorbic acid. In soft capsules, the active substance according to thepresent invention is preferably dissolved or suspended in suitableliquids, such as liquid polyethylene glycols, wherein stabilizers mayalso be added. For controlled release, the active substances accordingto the present invention may be incorporated in a pharmaceuticallyacceptable carrier matrix, or be enclosed in a membrane-definedreservoir which activates in vivo for appropriate release kinetics.

Suppositories are suitable standard dosage forms for rectal use; theseconsist of the active substance salt according to the present inventionwithin a base for suppositories which is based on natural or synthetictriglycerides having a suitable melting point, for example, cacaobutter, or on polyethylene glycols or suitable higher fatty alcohols.

Solutions of the active substance according to the present invention arepreferably suitable for parenteral administration. It is also possibleto use suspensions thereof, such as adequate oily injection suspensions.In this case, suitable lipophilic solvents or vehicles, such as oils,e.g., sesame oil, or synthetic fatty acid esters, e.g., ethyl oleate ortriglycerides, or aqueous injection suspensions comprisingviscosity-increasing substances, e.g., sodium carboxymethylcellulose,sorbitol, and/or dextran, and optionally also stabilizers are used.

Topically applicable pharmaceutical preparations of the salts accordingto the present invention, preferably of morphine-diclofenate (Formula1a) or diamorphine-diclofenate (Formula 1b), include creams, ointments,gels, pastes, foams, tinctures, and solutions comprising about 0.5 toabout 20% active substance according to the present invention. A saltaccording to the present invention, preferably morphine-diclofenate(Formula 1a) or diamorphine-diclofenate (Formula 1b), may also beincorporated into patches or so-called transdermal therapeutic systems(TTS); from these the active substance components act on the skin over adefined area of the body surface in occlusive manner at a controlledrelease rate and are appropriately brought to transdermal absorption.

The following Examples are given for illustration purposes and are notintended to limit the present invention:

METHODS OF PRODUCING THE SALTS EXAMPLE 1

An equimolar amount of an aqueous solution of diclofenac sodium salt isadded to an aqueous solution of morphine hydrochloride, this is broughtinto solution by stirring and optional heating. The forming morphinediclofenate precipitate is sucked off and dried over a molecular sievein a desiccator.

The content of both morphine and diclofenac can be detected in thecrystalline substance by IR spectroscopy.

The melting point of the salts amounts to about 143° C. and is thereforeclearly different from those of the starting materials (morphinehydrochloride: 255° C., diclofenac sodium salt: 280° C.)

EXAMPLE 2

Equimolar amounts of morphine base or diamorphine base and of[2-[(2,6-dichlorophenyl)-amino]-phenyl]-acetic acid are dissolved inethanol, mixed in a round-bottom flask, and evaporated to dryness in arotary evaporator. The evaporation residue is recrystallized fromethanol under addition of petroleum ether, sucked-off and vacuum-dried.

EXAMPLE 3

1 millimole of morphine hydrogen sulfate or diamorphine hydrogen sulfateis dissolved in water, made alkaline with an aqueous sodium bicarbonatesolution, and extracted with acetic ester. Also, 1 millimole ofdiclofenac sodium is dissolved in water, acidified with dilutehydrochloric acid, and extracted with acetic ester. Both extracts areseparately dried over anhydrous sodium sulfate. Subsequently, bothextracts are joined, mixed, and evaporated to dryness in theround-bottom flask at the rotary evaporator. The evaporation residue isrecrystallized from ethanol under addition of petroleum ether andvacuum-dried.

PROCESS OF PRODUCING A PHARMACEUTICAL PREPARATION EXAMPLE 4

For peroral administration morphine-diclofenate ordiamorphine-diclofenate is ground finely, and mixed homogeneously withpowdery carrier substances, such as lactose, saccharose, sorbitol,mannitol, or starches, until four times the amount is achieved. Singledoses, for example, 0.05 millimole of active substance equivalents, areweighed into gelatin capsules.

What is claimed is:
 1. A salt of a cationic narcotic analgesic with ananionic non-narcotic acid characterized in that the base of the narcoticanalgesic corresponds to the formula ##STR4## wherein R stands for H orCH₃ CO, and the non-narcotic analgesic belongs to the type ofsubstituted carboxylic acids.
 2. The salt according to claim 1characterized in that the anion of the non-narcotic analgesic of thetype substituted carboxylic acids is diclofenac, indomethacin, sulindac,ketoprofen, or fenbufen, preferably is diclofenac.
 3. A process for theproduction of the salt according to claim 1 or 2 characterized in thatthe base of the narcotic analgesic corresponds to formula 3, wherein Rstands for H or CH₃ CO or a suitable salt thereof, and is reacted withthe acid of the non-narcotic analgesic of the type substitutedcarboxylic acids or with a base salt thereof in an inert solvent at atemperature ranging from 0 to 100° C.
 4. The process according to claim3 characterized in that a salt of the non-narcotic analgesic of the typesubstituted carboxylic acids is used with bases which are more volatileor weaker than the base of the narcotic analgesic of formula 3, whereinR stands for H or CH₃ CO, or that a salt of the non-narcotic analgesicof the type substituted carboxylic acids is used with bases which formsalts with the non-narcotic analgesic of the type substituted carboxylicacids, which are more readily soluble than the salt according toclaim
 1. 5. The process according to claim 4 characterized in that anorganic ammonium salt or a metallic salt, preferably a calcium salt, isused as salt.
 6. The process according to any one of claims 3 to 5characterized in that a salt from the base of the narcotic analgesic offormula 3, wherein R stands for H or CH₃ CO, is used with acids whichare more volatile or weaker than the acid of the non-narcotic analgesicof the type substituted carboxylic acids, or that a salt from the baseof the narcotic analgesic of formula 3, wherein R stands for H or CH₃CO, is used with acids which form poorly soluble salts with metalcations, preferably with Ca²⁺.
 7. The process according to claim 6characterized in that a salt from the base of the narcotic analgesic offormula 3, wherein R stands for H or CH₃ CO, is used with inorganicacids, preferably a hydrochloride, sulfate, or phosphate, or that a saltfrom the base of the narcotic analgesic of formula 3, wherein R standsfor H or CH₃ CO, is used with organic acids, preferably a fumarate,maleate, or oxalate.
 8. The process according to any one of claims 3 to5 characterized in that diclofenac([2-[(2,6-dichlorophenyl)-amino]-phenyl]-acetic acid) is used as theacid of the non-narcotic analgesic of the type substituted carboxylicacids.
 9. A process for the production of a salt according to claim 1 or2 characterized in that an acid salt of the basic narcotic analgesic offormula 3, wherein R stands for H or CH₃ CO, preferably thehydrochloride, sulfate, or phosphate, is reacted with an ester of thenon-narcotic analgesic of the type substituted carboxylic acids,preferably a low-alkyl ester, in the presence of a base, preferablyNaOH, in an inert solvent at a temperature ranging from 0 to 100° C. 10.A process for the production of the salt according to claim 1 or 2characterized in that the base of the narcotic analgesic of formula 3,wherein R stands for H or CH₃ CO, is reacted with the acid of thenon-narcotic analgesic of the type substituted carboxylic acids in aninert solvent at a temperature ranging from 0 to 100° C.
 11. The processaccording to any one of claims 9 or 10 characterized in that the base ofthe narcotic analgesic of formula 3, wherein R stands for H or CH₃ CO,is used as raw alkaloid extract in admixture.
 12. A process for theproduction of the salt according to claim 1 or 2 characterized in thatthe cation or the base of the narcotic analgesic of formula 3, wherein Rstands for H or CH₃ CO, or the anion or the acid of the non-narcoticanalgesic of the type substituted carboxylic acids is bound to liquid orsolid charged or un-charged inorganic or organic adsorbents, preferablyion exchangers, and is reacted with the respective complementary anionicor cationic component in an inert solvent at a temperature ranging form0 to 100° C.
 13. The process according to any one of claims 3, 4, 5, 9,10 and 12 characterized in that at least equimolar amounts of reactantsare used.
 14. The process according to any one of claims 3, 4, 5, 9, 10and 12 characterized in that the reaction is carried out at roomtemperature and/or under inert gas atmosphere, preferably under nitrogenatmosphere.
 15. The process according to any one of claims 3, 4, 5, 9,10 and 12 characterized in that alcohols, ethers, ketones, carboxylicacid esters, amides, sulfoxides, chlorinated hydrocarbons, or mixturesof these solvents are used as inert solvents.
 16. The process accordingto claim 15 characterized in that low alkanols, preferably methanol orethanol are used as alcohols; di-low-alkyl ethers or cyclic ethers,preferably diethyl ether, dioxan or tetrahydrofuran are used as ethers;di-low-alkyl ketones, preferably acetone are used as ketones; low-alkylcarboxylic acid esters, preferably acetic acid ethyl ester are used ascarboxylic acid esters; N,N-di-low-alkyl amides, preferably N,N-dimethylformamide are used as amides; di-low-alkyl sulfoxides, preferablydimethyl sulfoxide are used as sulfoxides; and methylene chloride orchloroform are preferably used as chlorinated hydrocarbons.
 17. Apharmaceutical preparation characterized in that it comprises a saltaccording to claim 1 or 2 in addition to pharmaceutical adjuvants knownper se.
 18. The pharmaceutical preparation according to claim 17 forenteral, for example, oral or rectal administration, or for parenteral,for example, intravenous, intramuscular, subcutaneous, or topicalapplication.
 19. The use of the salt according to claim 1 or 2 ingalenic forms of preparation or for their production.
 20. The saltaccording to claim 1 or 2 for the therapeutic treatment of human andanimal organisms.
 21. The salt according to claim 1 or 2 for thetherapeutic treatment of pain.
 22. The pharmaceutical preparationaccording to claim 17 or 18 for the therapeutic treatment of human andanimal organisms.
 23. The pharmaceutical preparation according to claim17 or 18 for the therapeutic treatment of pain.
 24. A process for thetherapeutic treatment of human or animal organisms characterized in thata salt according to any one of claims 1 or 2 or a pharmaceuticalpreparation according to any one of claims 17 or 18 is used.
 25. Aprocess for the treatment of pain characterized in that a salt accordingto any one of claims 1 or 2 or a pharmaceutical preparation according toany one of claims 17 or 18 is used.